Dr Michaela Frye
Stem Cell Homeostasis and Disease
Tel: 01223 (7)60230
Michaela Frye completed her PhD in Frankfurt/Main in Germany in 2000 studying the role of epithelial defensins in Cystic Fibrosis. In 2001 she joined the lab of Fiona Watt as a Postdoctoral Fellow at the CR-UK London Research Institute where she developed her fascination for the question how stem cells in the skin are regulated. Michaela received a CR-UK Career Development Fellowship in 2007 when she started as a group leader at the WT-MRC Stem Cell Institute. She has renewed this fellowship in 2012 and is now a CR-UK Senior Fellow.
Stem cells are established during development and remain present in adulthood allowing the body to replace, restore and regenerate dead, damaged or diseased cells. Stem cells continuously maintain their population (self-renewal) while generating progeny (differentiation). During self-renewal stem cells have to avoid cell cycle exit and differentiation; whereas during differentiation stem cells must evade uncontrolled proliferation. Dissecting the regulatory pathways controlling the balance between these two states is fundamental to understanding how stem cell mis-regulation causes human diseases. While transcriptional regulation of stem cells is increasingly understood, little is known about how post-transcriptional mechanisms can influence stem cell maintenance. Post-transcriptional modifications are commonly found in non-coding RNA species and our recent studies identified cytosine-5 methylation of RNA as a novel mechanism regulating stem cell fate.
To dissect the cellular and molecular functions of cytosine-5 methylated RNA, we are using a combination of system-wide approaches, mouse models and in vitro differentiation assays. Our comprehensive approach will answer how post-transcriptional modification control stem cell fate in normal tissues and how aberrant cytosine-5 methylation pathways can cause human diseases.
Funding: Cancer Research UK, European Research Council, British Skin Foundation, Wellcome Trust
Plain EnglishMost tissues are maintained by stem cells throughout adult life. Stem cells are defined by their ability to continuously maintain their population (self-renewal) while generating differentiated progeny. During self-renewal, stem cells have to avoid cell cycle exit and differentiation; however, when differentiating they have to evade uncontrolled proliferation. How the balance between self-renewal and differentiation is regulated is not fully understood but yet highly relevant to a fundamental understanding of cell biology and human diseases. Aim of our research is to identify key factors regulating stem cell differentiation in adult tissues because important stem cell regulators are often mis-regulated in human diseases
Aberrant methylation of tRNAs links cellular stress to neuro-developmental diseases. Blanco S., Dietmann S., Flores J.V., Hussain S., Kutter C., Humphreys P., Lukk M., Lombard P., Treps L., Popis M., Kellner S., Hölter S.M., Garrett L., Wurst W., Becker L., Klopstock T., Fuchs H., Gailus-Durner V. , Hrabĕ de Angelis M., Káradóttir R.T., Helm M., Ule J., Gleeson J.G., Odom D.T., Frye.M. 2014. EMBO J. 33: 2020-39
NSun2-mediated cytosine-5 methylation of Vault non-coding RNA determines its processing into regulatory small RNAs. Hussain S., Sajini A.A., Blanco S., Dietmann S., Lombard P., Sugimoto Y., Paramor M., Gleeson J.G., Odom D.T., Ule J., and Frye M. 2013. Cell Reports. 4:255-61.
The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Hussain S., Tuorto F., Menon S., Blanco S., Watt S., Kudo N.R., Lyko F., and Frye M. 2013 Mol. Cell Biol. 33:1561-70
The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin. Driskell I., Oda H., Blanco S., Nascimento E.M., Humphreys P., and Frye M. 2011. EMBO J. 31:616-29.
The opposing transcriptional functions of Sin3A and c-Myc are required to maintain tissue homeostasis. Nascimento E.M., Cox C.L., MacArthur S., Hussain S., Trotter M., Blanco S., Menon S., Nichols J., Kübler B., Aznar Benitah S., Hendrich B., Odom D.T., and Frye M. 2011. Nature Cell Biology. 13:1395-405.
The RNA methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. Blanco S., Kurowski A., Nichols J., Watt F.M., Aznar Benitah S., Frye M. 2011. PLoS Genetics. 7:e1002403.
The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. Hussain S., Benavente S.B., Nascimento E., Dragoni I., Kurowski A., Gillich A., Humphreys P., Frye M. 2009. J Cell Biol. 186:27-40.
The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Frye M. and Watt F. M. 2006. Curr Biol. 16:971-81.